bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2026–03–22
seventeen papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Endogenous glucocorticoids and glucocorticoid receptor signaling: Dual regulators of PD-1/PD-L1 immunotherapy efficacy in the tumor microenvironment.
  2. Targeting MDSCs in cancer: emerging immunotherapeutic and metabolic strategies.
  3. The Role of Microenvironment in Bispecific Antibodies Treatment in Multiple Myeloma.
  4. The Exosome-Lactate-Lactylation Axis: A Metabolic-Epigenetic Circuit Driving Tumor Immune Evasion.
  5. Driving CAR therapies beyond T cells.
  6. The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations.
  7. Nanomedicines Reshape the Tumor Microenvironment: Multidimensional Strategies from Modulating "Barriers" to Metabolic Intervention.
  8. Neuro-tumor interactions in peripheral tumors.
  9. Tumor-Induced Splenic Remodeling: Mechanisms of Systemic Immunosuppression and Emerging Therapeutic Opportunities.
  10. Cancer-associated fibroblasts as key regulators of lipid metabolism in the tumour microenvironment.
  11. Cancer-associated fibroblasts: Orchestrators of the peritoneal metastatic microenvironment.
  12. Purinergic Signaling in Ovarian Carcinoma.
  13. Modulation of M1 macrophage polarization by Fe3O4@Cu2-xS engineering for improved tumor immunotherapy and MRI.
  14. S1P-S1PR1 signaling impairs CD8+ T cell metabolism and effector function in tumors.
  15. Breaking the immunosuppressive barrier: an armored CAR-M biotechnology with the original M1 phenotype dominance rescues antitumor immunity.
  16. B cell depletion promotes melanoma tumor growth in a CD4+ T cell-dependent manner.
  17. The intratumoral microbiome in colorectal cancer: origins, microenvironmental interactions, and new horizons in precision medicine.
  1. Chin Med J (Engl). 2026 Mar 17.
    Endogenous glucocorticoids and glucocorticoid receptor signaling: Dual regulators of PD-1/PD-L1 immunotherapy efficacy in the tumor microenvironment.
    Fanyu Guo, Benling Xu, Guangyu Chen, Jiaqi Liu, Quanli Gao.
       ABSTRACT: Immunotherapy targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) has significantly improved outcomes for various cancers, yet the emergence of resistance remains a major challenge. This review focuses on the dual role of endogenous glucocorticoids (GCs) and their receptor (GR) within the tumor microenvironment (TME), systematically elucidating the mechanisms by which they regulate responses to PD-1/PD-L1 therapy via the hypothalamic-pituitary-adrenal (HPA) axis, local synthesis and metabolism, and heterogeneity of GR signaling. We elaborate on the regulatory effects of the GC/GR signaling pathway on immune cells (such as cluster of differentiation 8 positive [CD8 + ] T cells, regulatory T cells [Tregs], dendritic cells, natural killer [NK] cells, and macrophages), and highlight the impact of GCs on PD-L1 expression, cytokine secretion, and the immunosuppressive microenvironment. This review also explores the controversial role of exogenous GCs in managing immune-related adverse events (irAEs) and their potential impact on therapeutic efficacy. The development of tissue-selective GR modulators holds promise for balancing immunosuppression while enhancing anti-tumor activity. A deeper understanding of the role of endogenous GCs in cancer immunotherapy is crucial for optimizing therapeutic strategies, overcoming resistance, and finally achieving precision in cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Glucocorticoid receptor; Glucocorticoids; PD-1/PD-L1 blockade; Tumor microenvironment
    DOI:  https://doi.org/10.1097/CM9.0000000000003956
  2. Front Immunol. 2026 ;17 1749965
    Targeting MDSCs in cancer: emerging immunotherapeutic and metabolic strategies.
    Shubhankar Dash, Patryk Firmanty, Monika Chomczyk, Vakul Mohanty, Wenxue Ma, Natalia Baran.
      Myeloid-derived suppressor cells (MDSCs) are a diverse group of immature myeloid cells critically involved in establishing an immunosuppressive environment within tumors. They impede effective anti-tumor immune responses through multiple mechanisms, including metabolic reprogramming, cytokine secretion, and immune checkpoint ligand expression. This immunosuppressive activity enables tumor progression and resistance to therapies, including immunotherapy. Recent advances reveal that targeting the metabolic pathways of MDSCs can impair their suppressive functions, offering promising strategies to enhance anti-cancer immunity. Approaches such as metabolic inhibition, direct depletion, blockade of recruitment and expansion, and promotion of differentiation into mature immune cells are under active investigation. Combining these strategies with immune checkpoint inhibitors and cell-based therapies, such as cancer vaccines and adoptive T-cell or NK-cell therapies, holds significant potential for overcoming immune resistance. Nonetheless, challenges including MDSC heterogeneity, toxicity, and biomarker validation must be addressed to optimize clinical translation. This review comprehensively covers current insights into the immune-metabolic mechanisms underpinning MDSC-mediated immunosuppression in the tumor microenvironment. It explores emerging therapeutic strategies aimed at targeting MDSCs through metabolic interventions, depletion, and modulation of their recruitment and differentiation. Furthermore, it discusses the integration of MDSC-targeted approaches with existing immunotherapies, highlights ongoing clinical trials, and assesses future directions, such as personalized, biomarker-driven treatments. Ultimately, this review underscores the potential of MDSC-focused therapies to significantly improve the efficacy of cancer immunotherapy and overcome mechanisms of tumor immune evasion.
    Keywords:  biomarker-driven therapy; cancer immunotherapy; immune checkpoint blockade; immunometabolism; metabolic reprogramming; myeloid-derived suppressor cells (MDSCs); tumor immune evasion; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2026.1749965
  3. Eur J Haematol. 2026 Mar 19.
    The Role of Microenvironment in Bispecific Antibodies Treatment in Multiple Myeloma.
    Serena Barachini, Raffaella Cassano Cassano, Francesca Ronca, Iacopo Petrini, Sara Galimberti, Gabriele Buda.
      Multiple myeloma (MM) is a clonal plasma cell malignancy that remains largely incurable despite major therapeutic advances. T-cell-redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T (CAR-T) cells have recently emerged as highly effective therapies in relapsed/refractory MM, inducing deep responses even in heavily pretreated patients. However, disease relapse, limited durability of response, and treatment-related toxicities remain frequent, underscoring the need to better understand mechanisms of resistance. Accumulating evidence indicates that the tumor microenvironment (TME) plays a central role in shaping BsAb efficacy in MM. Immunosuppressive cellular components, including regulatory T-cells, myeloid-derived suppressor cells, and dysfunctional antigen-presenting cells, as well as inhibitory cytokines, hypoxia, and metabolic constraints within the TME, profoundly impair T-cell activation, expansion, and persistence following BsAb engagement. In addition, chronic CD3 stimulation within the TME may promote T-cell exhaustion, contributing to suboptimal responses and disease progression. This review focuses on the dynamic interplay between BsAbs and the MM TME, highlighting how microenvironment-driven immune suppression, antigen escape, and impaired T-cell fitness influence clinical outcomes. We further discuss emerging strategies designed to overcome these barriers, including rational combination approaches, immunomodulatory agents, and next-generation trispecific antibodies that enhance co-stimulation or dual-antigen targeting. Understanding and therapeutically modulating the TME represents a critical step toward improving the depth, durability, and safety of BsAb-based therapies in MM.
    Keywords:  bispecific antibodies; drug resistance; multiple myeloma; tumor microenvironment
    DOI:  https://doi.org/10.1111/ejh.70168
  4. Compr Physiol. 2026 Apr;16(2): e70114
    The Exosome-Lactate-Lactylation Axis: A Metabolic-Epigenetic Circuit Driving Tumor Immune Evasion.
    Yuan Chen, Yuan Yuan, Zhen Zhang, Yihai Shi.
      Lactylation, as a post-translational modification, plays a role in tumor proliferation, metabolism, and the remodeling of the tumor microenvironment (TME). Emerging studies have revealed that exosomes regulate lactate metabolism by delivering functional molecules (such as lncRNAs, metabolic enzymes, etc.) thereby driving protein lactylation and establishing a novel intercellular communication mechanism. Furthermore, acidic microenvironments induce the release of immunosuppressive exosomes, amplifying immune evasion. Here, we summarize the current understanding of lactylation and exosome regulation in the TME and their impact on immune evasion. We explore the pivotal role of the "exosome-lactate-lactylation" axis in tumor metabolic reprogramming, metastasis, and immunosuppression, proposing targeted strategies against this axis.
    Keywords:  exosome; immune evasion; lactylation; metabolism; post‐translational modification
    DOI:  https://doi.org/10.1002/cph4.70114
  5. Trends Cancer. 2026 Mar 18. pii: S2405-8033(26)00039-7. [Epub ahead of print]
    Driving CAR therapies beyond T cells.
    Cecilie Ø Madsen, Thomas M Hulen, Maria Ormhøj, Sine R Hadrup, Inge M Svane, Özcan Met.
      Chimeric antigen receptor (CAR)-T cell therapy has reshaped cancer immunotherapy for hematological malignancies, yet progress in solid tumors remains limited. Physical barriers, antigen heterogeneity, and immunosuppressive tumor microenvironment restrict the activity and persistence of CAR-T cells, while safety concerns complicate target selection. Extending CAR technology to alternative immune lineages, such as macrophages, natural killer cells, tumor-infiltrating lymphocytes, and unconventional T cells, offers complementary mechanisms for tumor recognition, infiltration, and immune modulation. This review highlights recent advances in these emerging CAR platforms, compares their biological and translational features, and outlines how integrating cell-intrinsic properties with CAR design may guide the next generation of cellular immunotherapies for solid tumors.
    Keywords:  CAR-T therapy; NK cells; macrophages; tumor-infiltrating lymphocytes; unconventional T cells
    DOI:  https://doi.org/10.1016/j.trecan.2026.02.008
  6. Pathol Res Pract. 2026 Mar 09. pii: S0344-0338(26)00094-4. [Epub ahead of print]282 156443
    The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations.
    Amirhossein Faghih Ojaroodi, Samin Shokravi, Shabnam Eskandarzadeh, Armin Ghahremanzadeh, Fatemeh Alizadeh, Farinaz Amirikar, Golnaz Mobayen, Danial Mahrooghi, Masoud Lahouty, Karim Shamsasenjan, Mehdi Talebi.
      Tumor-induced hypoxia remains a pivotal characteristic of the tumor microenvironment (TME), significantly impacting immune cell functionality by fostering immunosuppression, tumor advancement, and resistance to therapies. This review consolidates established and emerging insights into how hypoxia, chiefly orchestrated by hypoxia-inducible factors (HIFs), metabolically and functionally reprograms key immune populations such as B cells, CD4 + T-cells, CD8 + T-cells, natural killer (NK) cells, regulatory T-cells (Tregs), and macrophages. We examine hypoxia-driven metabolic adaptations, signaling alterations, and evasion strategies, including enhanced glycolysis, lactate accumulation, and immune checkpoint upregulation. Furthermore, we integrate cutting-edge findings, such as hypoxia's modulation of NK cell cytotoxicity, immune metabolic reprogramming in the TME, HIF-mediated immune modulation, effector T-cell transcriptomic shifts akin to non-responsive tumor-infiltrating lymphocytes, and autophagy-dependent MHC-I suppression for immune evasion. These advancements underscore therapeutic opportunities in targeting hypoxia to bolster antitumor immunity and mitigate immunotherapy resistance in cancer.
    Keywords:  Anti-tumor response; HIF signaling; Hypoxia; Immunomodulation; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.prp.2026.156443
  7. Int J Nanomedicine. 2026 ;21 570411
    Nanomedicines Reshape the Tumor Microenvironment: Multidimensional Strategies from Modulating "Barriers" to Metabolic Intervention.
    Xinming Zhao, Dequan Liu, Guandu Li, Wenfei Xu, Guangzhen Wu.
      Nanoparticle-driven remodeling of the Tumor Microenvironment (TME) represents a transformative strategy in cancer therapy, shifting from traditional approaches to multidimensional modulation. This review explores how engineered nanoparticles precisely target and alter key TME components-including immune cells (eg, NK cells, dendritic cells, T cells), cancer-associated fibroblasts, and the extracellular matrix-to overcome "Chemical barriers" and "physical barriers". Furthermore, we highlight the pivotal role of nanoparticles in reprogramming TME metabolism, such as alleviating hypoxia, disrupting the Warburg effect, and modulating lipid and adenosine metabolism. By integrating immune activation with metabolic intervention, nanomedicines not only enhance anti-tumor immunity but also restore metabolic balance, offering a synergistic and potent therapeutic avenue for overcoming treatment resistance and inhibiting tumor progression.
    Keywords:  drug delivery; metabolic reprogramming; nanomedicine; tumor microenvironment
    DOI:  https://doi.org/10.2147/IJN.S570411
  8. Cancer Metastasis Rev. 2026 Mar 17. pii: 18. [Epub ahead of print]45(2):
    Neuro-tumor interactions in peripheral tumors.
    Xueshiyu Ma, Peixuan Ji, Jiahao Zheng, Shuqi Cai, Kan Xu, Yongwei Sun, Dejun Liu.
      The nervous system is now recognized as a pivotal regulator of cancer, marking a paradigm shift that recasts nerves from passive bystanders to active drivers within the tumor microenvironment (TME). This review defines the "neural niche," differentiating passive perineural invasion (PNI) from active tumor innervation. We examine how sympathetic signaling drives an "angio-metabolic switch" and immune evasion, whereas parasympathetic inputs exert context-dependent control over stemness and inflammation. We also highlight the underappreciated role of sensory neurons in promoting T-cell exhaustion via neuropeptides like calcitonin gene-related peptide (CGRP). Finally, we assess therapeutic strategies targeting neural dependence-from repurposing β-blockers to deploying nanotechnologies. Targeting neuro-tumor crosstalk offers a promising strategy to overcome therapeutic resistance and restore anti-tumor immunity.
    Keywords:  Nerve dependence; Neural invasion; Neuroscience; Neurotransmitter antagonists and tumor innervation
    DOI:  https://doi.org/10.1007/s10555-026-10321-6
  9. Adv Sci (Weinh). 2026 Mar 20. e00027
    Tumor-Induced Splenic Remodeling: Mechanisms of Systemic Immunosuppression and Emerging Therapeutic Opportunities.
    Yuehua Liu, Xiaoqian Nie, Xiaofei Gao.
      Despite the transformative impact of cancer immunotherapies such as immune checkpoint blockade, durable clinical responses remain limited. Increasing evidence indicates that antitumor immunity is governed not only by the tumor microenvironment, but also by systemic immune regulation mediated by peripheral immune organs. Among these, the spleen functions as a central blood-filtering immune hub that integrates immune activation with hematopoietic adaptation. During tumor progression, the spleen undergoes profound remodeling, shifting from a site of immune surveillance to a pro-tumorigenic immune compartment characterized by pathological extramedullary hematopoiesis, and sustained generation of immunosuppressive cell populations, including myeloid-derived suppressor cells. Continuous systemic export of these cells reinforces tumor immune evasion and constrains the efficacy of immune checkpoint blockade. In this review, we summarize current understanding of splenic structure and immunological function, delineate the mechanisms driving tumor-induced splenic remodeling, and examine its role in systemic immunosuppression and resistance to cancer immunotherapy. We further evaluate emerging therapeutic strategies aimed at targeting the spleen, highlighting both their translational potential and key biological barriers. Collectively, this work identifies tumor-induced splenic remodeling as a central yet underappreciated determinant of immunotherapy response and a promising target for next-generation immunotherapies.
    Keywords:  immunosuppression; myeloid‐derived suppressor cells; spleen‐targeted therapy; tumor‐induced splenic remodeling
    DOI:  https://doi.org/10.1002/advs.202600027
  10. Oncogene. 2026 Mar 21.
    Cancer-associated fibroblasts as key regulators of lipid metabolism in the tumour microenvironment.
    Jessamy Adams, Caterina M Suelzu, Gabriele Strusi, Justin Stebbing.
      Alterations in metabolism are recognised as a hallmark of cancer, allowing for rapid proliferation in an environment often hypoxic and short of nutrients. Cells within the tumour microenvironment (TME) often undergo metabolic alterations to adapt to these conditions, and this can also contribute to tumour progression. Cancer associated fibroblasts (CAFs) are amongst the most abundant non-cancerous cells in the TME and the main cells responsible for production and maintenance of the extracellular matrix. However, CAF subtypes can impact tumours in different ways and have been shown to play a role in alterations to lipid metabolism within tumours, being able to produce and secrete lipids, internalise them from the surrounding environment, and undergo fatty acid oxidation. Whilst this is still an emerging area of research, it appears that CAFs can have opposing roles in lipid metabolism in different types of cancer. Understanding the different metabolic pathways utilised in both CAFs and cancer cells and how external factors such as obesity and high fat diets influence them, could provide novel treatment avenues in the future. This review explores the literature surrounding lipid metabolism in CAFs and how this influences tumour progression and treatment resistance.
    DOI:  https://doi.org/10.1038/s41388-026-03733-9
  11. Crit Rev Oncol Hematol. 2026 Mar 15. pii: S1040-8428(26)00171-X. [Epub ahead of print]222 105284
    Cancer-associated fibroblasts: Orchestrators of the peritoneal metastatic microenvironment.
    Cheng Zhang, Ying Liu.
      Peritoneal metastasis (PM) represents a terminal stage of numerous abdominal malignancies, including gastric, colorectal, and ovarian cancers, and is associated with a dismal prognosis and limited therapeutic options. The peritoneal tumor microenvironment (TME) is a complex and dynamic ecosystem that actively governs cancer cell dissemination, implantation, and proliferation. Among the diverse cellular components of the TME, cancer-associated fibroblasts (CAFs) have emerged as principal regulators of this pro-tumorigenic niche. This review provides a comprehensive synthesis of current evidence regarding the multifaceted roles of CAFs in driving PM. The diverse origins of peritoneal CAFs were examined, with a particular focus on the pivotal process of mesothelial-to-mesenchymal transition (MMT), and the profound functional heterogeneity within the CAF population was explored. Moreover, the mechanisms through which CAFs promote metastasis were delineated, including the extensive remodeling of the extracellular matrix (ECM) that generates invasive pathways and modulates mechanotransduction. Furthermore, the complex CAF secretome, comprising cytokines, chemokines, growth factors, and extracellular vesicles that directly stimulate cancer cell motility, invasion, and survival, was investigated. Besides, the critical role of CAFs in modulating metabolic symbiosis, particularly through the provision of lipids that enhance cancer cell membrane fluidity and invasiveness, was also addressed. Finally, the mechanisms by which CAFs establish a profoundly immunosuppressive microenvironment by recruiting and polarizing myeloid cells, inhibiting T-cell function, and creating a physical barrier to immune surveillance were elucidated. In conclusion, CAFs are important regulators of the peritoneal metastatic cascade, coordinating a spectrum of pro-tumorigenic events that collectively facilitate tumor progression and therapeutic resistance.
    Keywords:  Cancer-associated fibroblasts; Extracellular matrix remodeling; Mesothelial-to-mesenchymal transition; Peritoneal metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105284
  12. Adv Pharm Bull. 2025 Nov;15(4): 779-792
    Purinergic Signaling in Ovarian Carcinoma.
    Angélica Sofía Martínez-Ramírez, José David Nuñez-Ríos, Ana Patricia Juárez-Mercado, Anaí Del Rocío Campos-Contreras, Francisco G Vázquez-Cuevas.
      Ovarian carcinoma (OC) is the most lethal gynecological cancer worldwide. Around 95% of patients exhibit recurrence five years after treatment; 80% experience recurrence within 18 months after first-line treatment, and progression-free survival rates have not changed over the past 40 years. New therapeutic approaches are imperative to face this complex disease. The purinergic system is a newly recognized element of the tumor microenvironment (TME), as it exhibits a pro-tumor role. Tumor cells release adenosine triphosphate (ATP) into the TME, where it exerts autocrine-paracrine actions that regulate several processes, including the induction of a metastatic phenotype, cell proliferation, and metabolic adaptations. In the extracellular milieu, ATP is converted to adenosine (ADO) by ectonucleotidases (CD39 and CD73), thereby significantly blocking the anti-tumor immune response through interactions with various immune cells. Recent analyses have focused on the diversity and plasticity of purinergic signaling in OC. This review outlines the disease, explains basic concepts of purinergic signaling, and summarizes experimental evidence that indicates purinergic elements may serve as potential targets for novel therapies to overcome OC.
    Keywords:  Adenosine; Extracellular ATP; Ovarian carcinoma; Purinergic receptors
    DOI:  https://doi.org/10.34172/apb.025.46032
  13. Colloids Surf B Biointerfaces. 2026 Mar 12. pii: S0927-7765(26)00202-X. [Epub ahead of print]263 115614
    Modulation of M1 macrophage polarization by Fe3O4@Cu2-xS engineering for improved tumor immunotherapy and MRI.
    Changzhou Shi, Yangang Zhu, Yanchen Wang, Nanxin Zhao, Zhen Zhang, Ye Wang, Manman Xie, Pingfu Hou, Jingjing Li.
      Tumor-associated macrophage (TAM)-mediated immunotherapy holds significant potential for cancer treatment. However, the presence of M2-like TAMs significantly hinders the efficacy of therapeutic interventions, making the reprogramming of M2 macrophages into the pro-inflammatory M1 phenotype critical. In this study, we proposed core-shell structured Fe3O4@Cu2-xS nanomaterials to engineer macrophages for enhanced tumor immunotherapy. Fe3O4@Cu2-xS-engineered M1 macrophages (Fe3O4@Cu2-xS@M1) could home to the tumor site and sustain their M1 phenotype within the tumor microenvironment (TME) while releasing NO, tumor necrosis factor-α (TNF-α), and other pro-inflammatory cytokines. A series of experimental results demonstrated that Fe3O4@Cu2-xS@M1 could not only facilitate the conversion of the neighbor Mø and M2 macrophages to the M1 phenotype in the TME which could not be realized by unengineered M1 macrophages, but also maintain the M1 macrophage state for a longer time thanks to the multiple pathways regulation, thereby activating antitumor immunity and inhibiting tumor progression better. The enhanced MRI contrast performance of Fe3O4@Cu2-xS facilitated non-invasive visualization of macrophage-driven immunotherapeutic processes in vivo. This study provided valuable insights into the use of nanomaterials with intrinsic immunomodulatory properties for effective cancer treatment.
    Keywords:  Engineering macrophage; MRI; Macrophage polarization; Nanoparticle; Tumor immunotherapy
    DOI:  https://doi.org/10.1016/j.colsurfb.2026.115614
  14. EMBO Rep. 2026 Mar 19.
    S1P-S1PR1 signaling impairs CD8+ T cell metabolism and effector function in tumors.
    Debashree Basak, Puspendu Ghosh, Anupam Gautam, Ishita Sarkar, Arpita Bhoumik, Soham Chowdhury, Shaun Mahanti, Anwesha Mandal, Rajeswari Chakraborty, Anwesha Kar, Snehanshu Chowdhury, Krishna Kumar, Shubhrajit Barman, Senthil Kumar Ganesan, Saikat Chakrabarti, Sandip Paul, Shilpak Chatterjee.
      Sphingosine-1-phosphate receptor 1 (S1PR1) signaling has been linked to the regulation of immunosuppressive cell populations within the tumor microenvironment (TME); however, its role in shaping anti-tumor CD8⁺ T cell responses remains poorly defined. Herein, we demonstrate that intratumoral CD8⁺ T cells express S1PR1, with expression predominantly enriched in the terminally exhausted subset. Transcriptomic profiling, combined with pharmacological inhibition and genetic knockdown, reveals that S1PR1-S1P signaling activates the PERK (protein kinase R (PKR)-like endoplasmic reticulum kinase)-CHOP (C/EBP homologous protein) axis of the endoplasmic reticulum stress response. CHOP, in turn, upregulates transcription of Map3k13 and Map3k15, triggering downstream MAPK signaling and culminating in activation of p38MAPK. Activation of this pathway impairs CD8⁺ T cell metabolism and effector function while increasing apoptotic susceptibility. This ultimately limits the persistence and accumulation of functional CD8⁺ T cells within the TME, thereby compromising their responsiveness to anti-PD-1 therapy. Targeting the S1PR1-S1P axis or its downstream effectors offers a promising strategy to improve cancer immunotherapy outcomes.
    Keywords:  CD8+ T Cells; ER Stress; S1P-S1PR1
    DOI:  https://doi.org/10.1038/s44319-026-00734-3
  15. Trends Biotechnol. 2026 Mar 18. pii: S0167-7799(26)00050-8. [Epub ahead of print]
    Breaking the immunosuppressive barrier: an armored CAR-M biotechnology with the original M1 phenotype dominance rescues antitumor immunity.
    Fuyu Du, Yuanhui Xu, Wenhui Chu, Jingjing Qiu, Meixi Jiang, Xinruo Wang, Dashan Guan, Maozhi Su, Anna He, Zixuan Ye, Yuqiong Xia, Xianghan Zhang, Zhongliang Wang, Pengbo Ning.
      Chimeric antigen receptor macrophages (CAR-Ms) hold promise for solid tumor immunotherapy, but their efficacy is limited by tumor microenvironment (TME)-driven M2 polarization. Current strategies rely on antigen-dependent activation or in vitro priming, which fail to sustain the M1 phenotype in the immunosuppressive TME. In this research article, we developed a TME-regulated CAR-M (TMER CAR-M) biotechnology by integrating an original M1 phenotype dominance into an active CAR-M (ACT CAR-M) platform. In tumor models, TMER CAR-M remodeled the TME, enhanced CD4+ and CD8+ T cell infiltration, increased the proportion of natural killer cells, reduced the frequency of regulatory T cells (Tregs) and myeloid-derived suppressor cells, effectively reversed the immunosuppressive state, and inhibited tumor growth in vivo. Crucially, human primary armored TMER CAR-M could effectively resist M2 reprogramming and reshape M2 macrophages. In conclusion, an armored TMER CAR-M biotechnology with the original M1 phenotype dominance overcomes TME immunosuppression through two mechanisms, including autonomous M1 maintenance and M2 reprogramming without antigen stimulation. This biotechnology bridges a critical gap in CAR-M therapy for solid tumors, offering a clinically translatable platform for immune-cold malignancies.
    Keywords:  M1 phenotype dominance; armored CAR-M biotechnology; immunotherapy; solid tumor; tumor microenvironment remodeling
    DOI:  https://doi.org/10.1016/j.tibtech.2026.02.011
  16. J Immunol. 2026 Mar 17. pii: vkag004. [Epub ahead of print]215(3):
    B cell depletion promotes melanoma tumor growth in a CD4+ T cell-dependent manner.
    Selin Oncul, Hani Lee, Shailbala Singh, Cassian Yee, Vahid Afshar-Kharghan.
      B cells constitute ∼15% to 20% of tumor-infiltrating lymphocytes in melanoma. Their presence in the tumor microenvironment correlates with improved survival and enhanced response to immune checkpoint blockade therapy. Yet, the functional contribution of B cells to melanoma immunity remains unclear. In this study, we showed that both genetic and antibody-mediated B cell depletion significantly promoted melanoma progression in mice. Immune profiling revealed that, although B cell percentages were reduced, IL-10-producing B regulatory cells (Bregs) persisted after depletion. However, the persistence of Bregs alone cannot explain the impact of B cell depletion on enhancing melanoma growth, as codepletion of B cells and CD4+ T cells, despite similar Breg levels, did not promote melanoma progression. B cell depletion also resulted in the accumulation of PD-1+ B cells, CD4+ T cells, and monocytic myeloid-derived suppressor cells into the tumor microenvironment, alongside a reduction in IFN-γ+CD8+ T cells, CXCL13+CD8+ T cells, and M1-like macrophages. Notably, plasma cell deficiency did not affect tumor growth, indicating that B cell-mediated antitumor activity is independent of antibody production. The tumor-promoting effect of B cell loss was at least partially CD4+ T cell dependent, as codepletion of B cells and CD4+ T cells reversed this phenotype and B cell depletion did not enhance tumor growth in Nu/Nu mice lacking mature T cells. Taken together, our findings reveal an antitumor role of B cells in melanoma and demonstrate that their loss promotes tumor progression through reprogramming of the tumor immune microenvironment.
    Keywords:  B cells; Bregs; CD4+ T cells; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.1093/jimmun/vkag004
  17. Front Immunol. 2026 ;17 1795736
    The intratumoral microbiome in colorectal cancer: origins, microenvironmental interactions, and new horizons in precision medicine.
    Xuemei Li, Qian Wang, Qiang Yuan, Li Wang.
      As a key functional component of the tumor microenvironment (TME), the intratumoral microbiome in colorectal cancer (CRC) has revolutionized the traditional paradigm of the "sterile tumor." Far from being mere "bystanders," these intratumoral microbes act as key drivers deeply implicated in remodeling the TME, influencing tumor progression, and determining therapeutic responses, thus necessitating a comprehensive synthesis of their complex biological characteristics and potential for clinical translation. Therefore, this review systematically summarizes the potential origins, community characteristics, and anatomical heterogeneity of the intratumoral microbiome. It further explores the precise mechanisms driving tumor progression, including the induction of genomic instability, metabolic reprogramming, epigenetic regulation, and immune microenvironment remodeling. We highlight the clinical utility of intratumoral microbes in CRC diagnosis, prognosis, and therapeutic prediction, while also introducing novel intervention strategies based on nanomedicine, engineered probiotics, and phage therapy. Finally, critical challenges such as contamination control in low-biomass samples, sampling heterogeneity, and the delineation of causality are scrutinized, aiming to provide new perspectives for the development of microbiome-guided precision medicine in CRC.
    Keywords:  Fusobacterium nucleatum; biomarkers; colorectal cancer; immunotherapy; intratumoral microbiome; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1795736
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